1. Field of the Invention
This invention relates to a novel carcinoma associated antigen (SK1) which is associated with various malignancies and monoclonal antibodies specific for epitopes on SK1.
2. Description of the Background Art
Murine monoclonal antibodies have been shown to mediate effective cytotoxicity to target cells in vitro; however, when utilized in vivo with humans, they have not achieved remarkable results. This is partially due to (i) the foreign nature of the injected murine proteins which leads to the development of a human anti-mouse antibody (HAMA) response, and (ii) the human effector functions which may not be fully activated by a murine antibody. In contrast, the dramatic effects which have been observed in systemically treating septic patients with purified human monoclonal or polyclonal antibodies (Ziegler, et al., The New England J. Med, 324:429-436, 1991; Kurtzberg, et al., Am. J. Pediatr. Hematol. Oncol., 9:299-301, 1987) and by intralesional therapy of melanoma suggests that the clinical use of human monoclonal antibodies (HuMAbs) (Irie, et al., Proc. Natl. Acad. Sci. USA, 83:8694-8698, 1986) will be successful. Thus, the potential use of human Mabs for cancer therapy is attractive.
Recent progress in the field of HuMAb technology has made it possible to generate numerous hybridomas of various specificities. Combined with knowledge gained in the understanding of the human immune response to cancer antigens (Lloyd, et al., Cancer Res., 49:3445-3451, 1989), several HuMAbs against tumor associated antigens (TAAs) have been produced and characterized. The reported tumor associated antigens recognized by HuMAbs include cell surface (Yoshikawa, et al., Jpn. J. Cancer Res. (Gann), 80:546-553, 1989; Yamaguchi, et al., Proc. Natl. Acad. Sci. USA, 84:2416-2420; Haspel, et al., Cancer Res., 45:3951-3961, 1985; Cote, et al., Proc. Natl. Acad. Sci. USA, 83:2959-2963, 1986; Glassy, Cancer Res., 47:5181-5188, 1987; and Borup-Christensen, et al., Cancer Detect. Prevent. Suppl., 1:207-215), cytoplasmic (Haspel, et al., Cancer Res., 45:3951-3961, 1985; Cote, et al., Proc. Natl. Acad. Sci. USA, 83:2959-2963, 1986; Glassy, Cancer Res., 47:5181-5188; Borup-Christensen, et al., Cancer Detect Prevent Suppl., 1:207-215, 1987; Kan-Mitchell, et al., Cancer Res., 49:4536-4541, 1989; and Yoshikawa, et al., Jpn. J. Cancer Res., 77:1122-1133, 1986), and nuclear antigens (McKnight, et al., Hum. Antibod. Hybridomas, 1:125-129, 1990).
At present, methods of limited effectiveness exist for treatment of various malignancies. Those drugs which are administered generally have severe side effects associated with their use. Accordingly, there exists a significant need to identify and purify an antigen associated with malignant diseases and to produce monoclonal antibodies which bind to epitopes on this antigen. Further, these antibodies are suitable agents for the diagnosis and treatment of malignancies expressing the SK1 antigen.
One way to ameliorate malignancies would be to suppress cells which preferentially express an antigen associated with carcinoma. This suppression could be accomplished, for example, by active immunization using an antigen, or a derivative thereof, preferentially present in malignant cells or by passive immunization by providing antibody to the antigen.
In order to provide a means to ameliorate malignant disease the invention provides substantially purified antigen which is preferentially expressed by malignant cells and monoclonal antibodies which bind to epitopes on the antigen. These monoclonal antibodies, if desired, can be labeled for therapeutic or diagnostic use.
An object of the present invention is to provide a method of detecting the carcinoma associated antigen (SK1) preferentially expressed in various malignant cells and tissues using a detectably labeled monoclonal antibody which binds to SK1 and determining whether the detectably labeled monoclonal antibody has bound to SK1.
Another object of the present invention is to provide methods for the in vitro and in vivo diagnosis of malignancy using detectably labeled monoclonal antibodies which react with an epitope present on SK1.
Another object of the invention is to provide methods for ameliorating malignant disease in an animal using unlabeled or therapeutically labeled monoclonal antibodies which react with SK1.
Alternatively, the invention provides methods for ameliorating malignant disease in an animal by inducing an immune response to the malignancy by immunizing the animal with SK1.
The present invention thus relates to a method of detecting SK1 which comprises contacting a source suspected of containing SK1 with a diagnostically effective amount of detectably labeled monoclonal antibody, or fragment thereof, having the specificity of a monoclonal antibody of the invention and determining whether the antibody binds to the source.
The invention further relates to a method of suppressing malignant disease in an animal which comprises administering to the animal a therapeutically effective amount of a (1) monoclonal antibody, or fragment thereof, wherein the antibody has the specificity of a monoclonal antibody of the invention, or (2) SK1.
A major advantage in the therapeutic and diagnostic use of SK1 and mono-clonal antibodies which bind to epitopes of SK1 is that the SK1 antigen occurs at high frequency in malignant cells. Consequently, there is a much greater probability of binding occurring to a malignant cell than to a normal cell. As a result of this fact, it is possible to use concentrations of the monoclonal antibody of the invention which are clinically effective, but pose minimal or no risk to normal host cells.